Genes From Neanderthals Linked to Lower Pain Threshold

Neanderthal introgression

Thanks to fossil and DNA evidence, we now know that Neanderthals lived alongside early humans for at least part of their existence. It’s possible that they lived very closely, in fact. “Some of us carry, in DNA, sequences that are genetically closer to Neanderthals than to Homo sapiens. These sequences are usually rather short and, when summed over the whole genome of an individual, represent only a few percents of the DNA of that individual,” Pierre Faux, a senior researcher at the French National Institute for Agriculture, Food and Environment, says.

The Neanderthal introgression hypothesis suggests that these sequences found in modern humans are a result of Homo sapiens interbreeding with Neanderthals approximately 50,000 years ago. “Recent advances in science, in particular thanks to the sequencing of Neanderthal genomes with high precision, made that hypothesis a likely explanation for the closeness of these sequences.”

Increased access to high-quality Neanderthal genomes is helping scientists to understand our ancient ancestors’ lifestyles and biology. While 50,000 years have passed since we last shared a planet with Neanderthals, comparing their genomes with our own can help to shed light on common experiences, such as pain.  

The voltage-gated sodium channel Nav1.7 plays a key role in nociception – the processing of noxious stimuli such as injury or temperature by the central and peripheral nervous system. Pain is the unique, subjective experience that arises as a result of this processing. Mutations in the gene that encode Nav1.7, called SCN9A, are of clinical interest due to their association with human pain disorders, often manifesting either as an insensitivity to pain or a heightened experience of pain.

Several years ago, scientists led by Hugo Zeberg, assistant professor at the Karolinska Institute, discovered three variants in SCN9A in sequenced Neanderthal genomes and in some modern-day humans. These variants, M932L, V991L and D1908G, were associated with greater sensitivity to pain in participants from the UK Biobank (UKBB).

The M932L, V991L and D1908G variants are quite rare in European populations, such as the UKBB dataset. In a new study published in Nature, Faux and colleagues sought to replicate and extend the work of Zeberg et al. by analyzing pain thresholds in populations where these mutations are more frequent, and to understand the sensory responses that are affected by them.

All three SCN9A variants associated with lower pain thresholds

Over recent years, the research team has been conducting genetic analyses on volunteers from Brazil, Colombia, Chile, Peru and Mexico, collectively known as the CANDELA cohort. They have also been studying experimental pain specifically in the Colombian participants, using a technique known as quantitative sensory testing, or QST. This protocol involves assessing several pain thresholds at baseline level, and then re-testing them after the application of mustard oil.

The researchers characterized Neanderthal introgression in SCN9A in both cohorts, discovering that the three variants were common across all groups, but were more common in populations with higher portions of Native American ancestry, like the Peruvian population. Applying the QST protocol, they found that all three SCN9A variants were associated with a lower pain threshold in response to skin picking after mustard oil application. This response was not observed in response to the application of heat, or pressure, helping the scientists to decipher how these variants affect sensory responses.

“With an objective measurement of sensitivity (rather than a subjective one) and working with a population where these mutations are frequent, we confirmed the Neanderthal origin of the mutations and their association to increased sensitivity,” describes Dr. Kaustubh Adhikari, a lecturer in statistics at the Open University and co-author of the study. “On top of that, we identified that mechanical pain after skin sensitization was the type of pain affected by these mutations.”

The opening of sodium channels in the neuronal membrane allows sodium to travel into the neuron, generating an electrical current. This electrical current is the driving force behind action potentials which, put simply, allow neurons to communicate with one another. “In the case of sensory nerves, their terminals are in the skin and convert signals from the environment that could cause injury such as sharp mechanical stimuli, high temperature or chemicals into action potentials,” explains Dr. David Bennett, professor of neurology and neurobiology at Nuffield Department of Clinical Neurosciences, University of Oxford, Senior Wellcome Clinical Scientist and Honorary Consultant Neurologist. “We are proposing that genetic changes alter the structure and ultimately the function of these sodium channels so that they are more likely to open, meaning neurons are more likely to generate action potentials in response to stimulation such as mechanical force applied to the skin by a sharp object. People will experience this as a lowered pain threshold, i.e., a lower force evokes the perception of pain.”

Population genetics and neuroscience intertwine  

Pain is typically an unpleasant experience, but it is an important one. Our body’s response to painful stimuli helps us to defend against or move away from the potentially harmful stimulus. Do the SCN9A mutations confer an evolutionary advantage? Is that why they have persisted for thousands of generations? Right now, the team aren’t sure, but they hypothesize natural selection is at play. “We don’t have a clear idea yet on how it worked. For instance, the same mutations may have affected a completely different trait too. In such case, selection could have played on that unidentified trait, and impacted pain sensitivity only in an indirect way,” Faux says, adding that it is currently a challenge to further investigate these evolutionary aspects. Instead, the researchers are focusing on understanding how other genes affect pain perception.

This research intertwines two interesting and constantly evolving research fields – population genetics and neuroscience. “In population genetics, our interest is in reconstructing the past using today’s genomes. The likely intermixing of Neanderthals with modern humans is thus a major area of interest,” says Andres Ruiz-Linares, professor of human genetics at the Genetics, Evolution and Environment department at UCL. “Researchers’ interest in the experience of pain in neuroscience goes beyond genetics: chronic pain, for instance, is a huge health problem, and results from various factors in addition to genetics: environment, past experience and psychological variables.”

Understanding how genetic mutations might contribute to phenotypes such as pain sensitivity is, the researchers hope, an important step towards the development of better pain treatments.

Pierre Faux, Andres Ruiz-Linares, Davi Bennett and Kaustubh Adhikari were speaking to Molly Campbell, Senior Science Writer for Technology Networks.

Reference: Faux P, Ding L, Ramirez-Aristeguieta LM, et al. Neanderthal introgression in SCN9A impacts mechanical pain sensitivity. Comms Bio. 2023;6(1):958. doi: 10.1038/s42003-023-05286-z